Ring-closing olefin metathesis (RCM) has in the mean time advanced to become one of the most successful synthesis methods by which cyclic structures of all sizes and with a plurality of functional groups can be efficiently synthesised. This property has made this transformation of substances a central tool in the modern chemistry of natural substances, which constitutes a reliable criterion for its exceptional usefulness in synthesis (a) R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413; b) A. Fürstner, Angew. Chem. Int. Ed., 2000, 39, 3012; c) S. J. Connon, S. Blechert, Angew. Chem. Int. Ed., 2003, 42, 1900).
Hitherto, only homogeneous catalysts (predominantly Ru complexes) have been considered for the transformation of functionalised olefins, as they have a far higher group tolerance than their heterogeneous metal oxide-based analogues. However, the concentrations of the homogeneous catalysts used are typically in the one-digit molar percentage range, which makes it essential to separate them efficiently from the product for economic and toxicological reasons.
The state of the art is the immobilisation of the homogeneous catalysts on solid carrier materials which can be separated off by filtration after the reaction has taken place, or the separation and recycling of the homogeneous catalyst by multi-phase catalysis, a process in which the catalyst is immobilised in one phase (stationary phase) and the products may be obtained from the other phase (known as the mobile phase in the continuous process). Two special issues have already been published on the subject of two-phase catalysis and related technologies: a) Catalysis Today 1998, 42, issue 2; b) Chem. Rev. 2002, 102, October issue). The latter strategy has been very successfully implemented in the Shell Higher Olefin Process or in the Ruhrchemie-Rhöne-Poulenc Process. The two processes are characterised in that only gaseous starting materials are used which are converted into liquid products. These can then be separated off as a phase in their own right.
However, this method is by no means generally applicable, as the chemical-physical properties of starting materials and corresponding target molecules are often very similar. This is true particularly of olefin ring-closing metathesis. In addition, reactants which are liquid and solid at ambient temperature—the aggregate states of nearly all fine chemicals—are far more difficult to react efficiently in multi-phase catalysis, essentially because an additional solvent has to be used. This is needed in order to intensify contact with the catalyst phase and produce a suitable concentration of the substrates at the reaction site. Precisely for efficiently performing ring-closing olefin metathesis both functions of the solvent are of fundamental importance for a high throughput and selectivity (cyclisation vs. oligomer formation). The incorporation of another solvent phase, however, leads to a number of problems:                1. The products have to be freed from the solvent, a process which generally exposes them to thermal loading, which often reduces the yield.        2. It often proves very difficult to remove the last traces of solvent from the product, and this is a particular problem for pharmaceutical production lines.        3. The widely used metathesis catalysts have insufficiently selective distribution coefficients for conventional two-phase systems (liquid-liquid systems), with the result that there is undesirable leaching of catalyst into the substrate/product phase. As a result of this extractive removal, not only is the activity of the catalytic system reduced but there is also contamination of the product with catalyst, which is unacceptable in many branches of fine chemistry.        4. Particularly the mobile solvent used for a continuous process must be extremely clean, as otherwise impurities from it build up in the catalytically active phase, and in this way catalyst deactivation may be accelerated. However, highly pure organic solvents are very expensive and hence uneconomical. There is also the factor than in ring-closing metathesis of rings of average size (8-11 ring members) and large size (greater than or equal to 12 ring members) it is essential to work with very high dilutions so as to counteract reactions of oligomerisation.        5. In view of their flammability and high volatility conventional solvents constitute an additional potential risk.        
The aim of the present invention was therefore to solve the problems mentioned above and to provide a process which is suitable for the continuous olefin ring-closing metathesis of both liquid and solid substrates.
Supercritical carbon dioxide has already proved itself as a solvent for olefin metathesis reactions of a whole range of cyclisable substrates. It is not only very good value (even in highly pure form), non-toxic and non-flammable but also allows controlled manipulation of the monomer-oligomer equilibrium in RCM, by varying the fluid density used ((a) A. Fürstner, L. Ackermann, K Beck, H. Hori, D. Koch, K. Langemann, M. Liebl, C. Six, W. Leitner, J. Am. Chem. Soc. 2001, 123, 9000-9006, b) Fürstner et al., Selective Olefin Metathesis of Bifunctional or Polyfunctional Substrates in compressed Carbon Dioxide as Reaction Medium, U.S. Pat. No. 6,348,551; c) DeSimone et al., Olefin Metathesis Reactions in Carbon Dioxide Medium, U.S. Pat. No. 5,840,820). When compressed carbon dioxide is used on its own as the reaction medium, two properties in particular are problematic for the ring-closing olefin metathesis.                1. On the one hand, the supercritical carbon dioxide does not have good dissolving properties on the currently most active metathesis catalysts, with the result that the conversion rates are correspondingly low. Quite apart from olefin metathesis this has led to the development of homogeneous catalysts with solubilising perfluorinated chains ((a) S. Kainz, D. Koch, W. Baumann, W. Leitner, Angew. Chem. Int. Ed. Engl. 1997, 36, 1628-1630; b) Holmes et al., Use of Compressed CO2 in Chemical Reactions, U.S. Pat. No. 6,458,985 B1). However, such catalysts are complicated to synthesise and are therefore very expensive.        2. The solubility of the currently most active metathesis catalysts under reaction conditions which are suitable for efficiently reacting non-volatile substrates is still high enough to require separation of the catalyst from the product. But this cannot be done without additional adjuvants in subsequent processes. This is also the reason why immobilisation on a solid phase was developed for reactions in compressed carbon dioxide, the solid phase containing both CO2-philic and CO2-phobic parts of the molecule, so as on the one hand to achieve good transportation of the substance at the catalytically active centres while on the other hand ensuring efficient separation. (DeSimone et al., Carbon Dioxide-Soluble Polymers and Swellable Polymers for Carbon Dioxide Applications, U.S. Pat. No. 6,747,179 B1). As a limiting factor it must be stated, however, that the catalytic effectiveness of this concept is in no way characterised in the above-mentioned patent.        
Ionic liquids are also described in the chemical literature as potential reaction media for carrying out olefin ring-closing metathesis reactions. Their major advantage is in their lack of volatility below their decomposition temperature and in their non-flammability. In addition, many examples are immiscible with conventional solvents, thus enabling the product to be easily isolated by extraction ((a) R. C. Buijsman, E. van Vuuren, J. G. Sterrenburg, Org. Lett. 2001, 3, 3785-3787, b) Gürtler et al., α, ω-Diene Metathesis in the Presence of Ionic Liquids, U.S. Pat. No. 6,756,500 B1). The most widely used Grubbs catalysts however exhibit significant leaching during extractive working up with conventional organic solvents, with the result that they can be recycled a maximum of once or twice. Building on this experience, in two independent studies imidazolium fragments were integrated in the most active catalyst structures currently known, which for the first time synthesised a precatalyst which can be recycled in ionic liquids (a) N. Audic, H. Clavier, M. Mauduit, J.-C. Guillemin, J. Am. Chem. Soc. 2003, 125, 9248-9249; b) Q. Yao, Y. Zhang, Angew. Chem Int. Ed. 2003, 42, 3395-3398). Apart from the use of highly volatile, combustible and in some cases toxic solvents for the extractive working up, however, there are also other disadvantages:                1. In a fast chemical reaction at the catalyst centre (which is dissolved in the ionic liquid) the mass transfer frequently limits the speed of the reaction as a whole. This problem is generally considerably more serious than in reactions in the two-phase system with two organic phases or one organic and one aqueous phase, as the relatively high viscosity of the ionic liquid leads to a low coefficient of diffusion and relatively large droplets in the stirred system. Both these effects undesirably influence the mass transfer of the educt to the catalyst centre.        2. Ionic liquids are significantly more expensive than water and the majority of organic solvents. From the point of view of the industrial user, this demands total recovery not only of the transition metal catalyst used but also of the ionic liquid used in the system. Against this background, the greater or lesser cross-solubility of ionic liquids in the organic educts and products is problematic, and is particularly serious when educts and products themselves have a certain polarity. In a continuous process, there may thus be a constant loss of ionic liquid and catalyst into the products.        
In 1999 the Brennecke and Beckman research groups described the phase characteristics of two-phase mixtures of ionic liquids with supercritical carbon dioxide (L. A. Blanchard, D. Hancu, E. J. Beckman, J. F. Brennecke, Nature 1999, 399, 28-29). They were able to show that supercritical CO2 dissolves easily in some ionic liquids, while the same ionic liquids have no detectable solubility in supercritical CO2. Moreover, in this publication, the authors described the possibility of extracting high-boiling substances from ionic liquids, using supercritical CO2. No contamination of the extract with ionic liquids could be detected.
The Jessop working group used extraction with supercritical CO2 to isolate the products from ionic liquids following a hydrating reaction with neutral ruthenium catalysts (R. A. Brown, P. Pollett, E. McKoon, C. A. Eckert, C. L. Liotta, P. G. Jessop, J. Am Chem. Soc. 2001, 123, 1254). This concept was expanded by Baker and Tumas, who described the successful hydrogenation of cyclohexene and 1-decene using the neutral Wilkinson catalyst RhCl(PPh3)3 in the two-phase system of [BMIM][PF6]/supercritical carbon dioxide. However, comparison tests carried out by these authors showed that in the presence of supercritical CO2, generally lower or, at best, equally high activities are found for the catalysts. The conversion rates in the [BMIM][PF6]/supercritical carbon dioxide system correspond in favourable cases to the values achieved in the [BMIM][PF6]/n-hexane system (F. Liu, M. B. Abrams, R. T. Baker, W. Tumas, Chem. Commun. 2001, 433). Another catalytic study in a two-phase system consisting of supercritical carbon dioxide and an ionic liquid was published by Cole-Hamilton and colleagues (Cole-Hamilton et al., Catalysis in an Ionic Fluid, Supercritical Fluid Two Phase System, WO 02/02218 A1; M. F. Sellin, P. B. Webb, D. J. Cole Hamilton, Chem Commun. 2001, 781). The group investigated the hydroformylation of 1-hexene, 1-octene and 1-nonene with anionic Rh complexes. However, their method is restricted to systems in which there is at least one reactant which is gaseous under normal conditions.
Definition of Terms in the Figures:    Umsatz=conversion    Reaktionstemperatur=reaction temperature    Edukt-beladener CO2-Strom=educt-charged CO2 current    SFC-Pumpe=SFC pump    Edukt-Reservoir=educt reservoir    Kohlendioxid=carbon dioxide    unbeladener CO2-Strom=uncharged CO2 current    pneumatisches Ventil (elektromagnetisch schaltbar)=pneumatic valve (electromagnetically controlled)    Reaktor=reactor    Produkt=product